Pharma companies developing treatments for lung cancer should design more nuanced clinical trials that can provide better data about how the drugs are used in combination with surgery, a panel of outside advisors to the FDA unanimously voted on Thursday.
The panel’s 11-0 vote came after hours of discussion about how immune checkpoint therapies like AstraZeneca’s Imfinzi should be administered to early-stage cancer patients who get surgery to remove their tumors. The FDA also asked the experts to weigh in on AstraZeneca’s drug, which the agency is reviewing to decide whether it should be approved before and after surgery for early-stage lung cancer.
As pharmaceutical companies have been pushing their blockbuster cancer drugs into earlier stages of cancer, the FDA has been concerned that trials of checkpoint inhibitors given perioperatively — meaning both before and after surgery — fail to separate out the impact of each part of treatment. According to the FDA, that may be leading to over-treatment and unnecessary toxicities to patients. Experts said it also adds to the cost.
“My hope is that we eliminate some of this ambiguity with the patient-physician conversations. It’s a big burden to put on patients to have them make the decision. And I think that more is not always more,” said advisory committee member Pamela Kunz of Yale Cancer Center. “I hope that the FDA considers this conversation in other solid tumors.”
While they want more nuanced trials for future approvals, experts on the advisory committee said that asking AstraZeneca to run a second trial would delay access to a regimen that showed benefit — even though it’s unclear how much each phase of the therapy helped.
“You can’t unring this bell,” said advisory committee member Ravi Madan of the National Cancer Institute. “I do hope that we’ll get more understanding from ongoing trials and future data and we can revisit this. But I think to delay this at this point is very complicated for patients and their providers.”
Incentives and side effects
Narrowing how the drugs are used could help patients, and might also hurt drug company revenue. Yale’s Kunz suggested that companies might have no financial reasons to conduct research that would limit the use of their products.
“There’s generally a financial incentive for the applicant to provide longer treatments, certainly a year in the adjuvant setting,” she said.
Daniel Spratt of Case Western Reserve argued that while running a wider trial would add time, it could potentially prevent a substantial financial burden for patients, citing the extra time that patients spend on the drug under the current regimen.
“That’s a year of therapy. The financial toxicity part of this is substantial. It’s hundreds of thousands of dollars,” Spratt said. AstraZeneca reported $2.26 billion in sales of Imfinzi in the first half of the year, and the drug is approved for the treatment of a variety of solid tumors.
“About two days of revenue you could generate probably enough to get one more arm of trial for two years of data,” he said.
There’s also another lurking issue: The biggest player in the space, Merck, has already received FDA approval for its drug Keytruda before and after surgery in early-stage lung cancer without discerning the contribution of each phase, though its trial showed Keytruda improved survival outcomes.
“The elephant in the room obviously is the KEYNOTE-671 trial, which was approved,” said Erin Larkins, FDA acting director for the Division of Oncology 2.
AstraZeneca has asked the FDA to approve Imfinzi’s use before and after surgery for certain stages of lung cancer. In its key clinical trial, giving Imfinzi on top of chemotherapy before surgery, followed by as much as a year of the drug after surgery, cut the risk of certain complications, including cancer recurrence, by 32%.
Bristol Myers Squibb is also expecting an FDA decision by Oct. 8 on perioperative Opdivo in similar stages of lung cancer.
At the meeting, FDA staff said they had recommended that AstraZeneca run a trial separating the effects of when the drug is given around surgery, but that the drugmaker did not do so. And the agency pointed to recent results from a study sponsored by a Canadian group that suggested Imfinzi did not improve outcomes when given after surgery in certain early-stage lung cancer patients.
Future Trials
The ramifications of the advisory committee’s recommendations extend beyond AstraZeneca. Pharma companies have looked to grow their checkpoint inhibitor business by moving to earlier stages of lung cancer as well as in other solid tumor cancers.
The FDA suggested that, in the future, drugmakers could run three- or four-arm trials, which may need more patients or take more time, but would clearly delineate the benefits of giving therapy before surgery, after surgery, or both. Advisory committee members raised concerns of such trial designs potentially prolonging drug development times and increasing costs.
“We’re going to cost millions of dollars by making this decision, and potentially delaying drug development. We have to find better surrogate markers, particularly in this space” said Christopher Lieu of the University of Colorado Cancer Center. “Because otherwise we’re going to start delaying those approvals by five, six years.”
One solution Yale’s Kunz raised was using the accelerated approval pathway with a confirmatory study, making the treatment available but also addressing the question about whether both phases of treatment contribute to treatment.